GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease.

• ClinicalTrials.gov Identifier: NCT05686551
• Recruitment Status: Recruiting
• First Posted: January 17, 2023
• Last Update Posted: April 29, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: December 16, 2022
• First Posted Date: January 17, 2023
• Last Update Posted Date: April 29, 2024
• Actual Study Start Date: February 3, 2023
• Estimated Primary Completion Date: February 28, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 6, 2023)

• Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale [ Time Frame: Up to Approximately 24 Months ]
• Change from baseline in clinical laboratory results - Cerebrospinal fluid (CSF) White Blood Cell (WBC) (1/uL) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
• Change from baseline in clinical laboratory results Cerebrospinal fluid (CSF) protein (g/L) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
• Change in baseline in structural MRI assessing any new abnormalities including radiographic features consistent with hydrocephalus and other relevant MRI safety findings [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 ]
• Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 [ Time Frame: Baseline and Month 9 ]
• Change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. sites) at 16 months [ Time Frame: Baseline to 16 Months ]
  Change in scores on the scale
• Change from baseline in Total Functional Capacity (TFC) Scores (U.S. sites) at 16 months [ Time Frame: Baseline to 16 Months ]
  Change in scores on the scale

Original Primary Outcome Measures (submitted: January 6, 2023)

• Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale [ Time Frame: Up to Approximately 24 Months ]
• Change from baseline in clinical laboratory results - Cerebrospinal fluid (CSF) White Blood Cell (WBC) (1/uL) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
• Change from baseline in clinical laboratory results Cerebrospinal fluid (CSF) protein (g/L) [ Time Frame: From Baseline Visit (Day 1), and Months 4, 8, 9, 12, 16 ]
• Change in baseline in structural MRI assessing any new abnormalities including radiographic features consistent with hydrocephalus and other relevant MRI safety findings [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]
• Percentage change from baseline in geometric means of CSF mHTT protein levels at Month 9 [ Time Frame: Baseline and Month 9 ]
• Change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores (non-U.S. sites) at 16 months [ Time Frame: Up to Approximately 16 Months ]
  Change in scores on the scale
• Change from baseline in Total Functional Capacity (TFC) Scores (U.S. sites) at 16 months [ Time Frame: Baseline and 16 Months ]
  Change in scores on the scale

Current Secondary Outcome Measures (submitted: November 6, 2023)

• Change from baseline in MoCA Scores [ Time Frame: From Baseline, Months 4, 8, 12, 16 and up to approximately Month 24 ]
• Percentage of participants with suicidal ideation or behavior as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct [ Time Frame: Up to Approximately 24 Months ]
• Change from baseline at 16 months for the assessments of TFC (non-U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of cUHDRS (U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of Symbol Digit Modalities Test (SDMT) Scores [ Time Frame: Baseline to 16 Months ]
• Change from Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of Total Motor Score (TMS) [ Time Frame: Baseline to 16 Months ]
• Change from baseline in CSF Neurofilament light Chain (NfL) levels at 16 months [ Time Frame: Baseline to 16 Months ]
• Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 ]
• Titers determined if ADAs are identified [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 24 ]

Original Secondary Outcome Measures (submitted: January 6, 2023)

• Change from baseline in MoCA Scores [ Time Frame: From Baseline, Months 4, 8, 12, 16 and up to approximately Month 36 ]
• Percentage of participants with suicidal ideation or behavior as assessed by C-SSRS score at each visit, including detailed focus on any individual cases identified as having severe ideation or behavior during the study conduct [ Time Frame: Up to Approximately 24 Months ]
• Change from baseline at 16 months for the assessments of TFC (non-U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of cUHDRS (U.S. sites) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of Symbol Digit Modalities Test (SDMT) Scores [ Time Frame: Baseline to 16 Months ]
• Change from Baseline at 16 Months for the Assessments of Stroop Word Reading (SWR) Scores [ Time Frame: Baseline to 16 Months ]
• Change from baseline at 16 months for the assessments of Total Motor Score (TMS) [ Time Frame: Baseline to 16 Months ]
• Change from baseline in CSF Neurofilament light Chain (NfL) levels at 16 months [ Time Frame: Baseline to 16 Months ]
• Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence of ADAs at baseline [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]
• Titers determined if ADAs are identified [ Time Frame: From Baseline, Months 4, 8, 12, 16 and Up to Approximately Month 36 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington's Disease.
• Official Title: A Phase II, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen in Individuals With Prodromal and Early Manifest Huntington's Disease
• Brief Summary: This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Huntington Disease

Intervention

• Drug: Tominersen 60 mg
  60 mg tominersen administered intrathecally every 16 weeks
• Drug: Placebo
  Matching placebo administered intrathecally every 16 weeks
• Drug: Tominersen 100 mg
  100 mg tominersen administered intrathecally every 16 weeks

Study Arms

• Experimental: Tominersen 60 mg
  Intervention: Drug: Tominersen 60 mg
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Experimental: Tominersen 100 mg
  Intervention: Drug: Tominersen 100 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 6, 2023): 300
• Original Estimated Enrollment (submitted: January 6, 2023): 360
• Estimated Study Completion Date: April 1, 2027
• Estimated Primary Completion Date: February 28, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria

-Huntington's disease (HD) gene expansion mutation carrier status with a CAP score of 400-500 inclusive

Either:

• Prodromal HD (defined as DCL 2 to 3, Independence Scale (IS) ⩾70, and ⩾TFC8); or
• Early manifest HD (defined as DCL 4, Independence Scale (IS) ⩾70, and ⩾TFC8);
• Total body weight > 40 kg and a body mass index within the range of 18-32 kg/m2
• Study Companion

Key Exclusion Criteria

• Current or previous use of an ASO (including small interfering RNA) or any HTT lowering therapy (including tominersen)
• Anti-platelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin (unless </= 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin
• History of gene therapy, cell transplantation, or brain surgery
• Hydrocephalus
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug
• History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 25 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: BN42489 https://forpatients.roche.com/; 888-662-6728 (U.S. Only); global-roche-genentech-trials@gene.com

• Listed Location Countries: Argentina, Australia, Austria, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT05686551
• Other Study ID Numbers: BN42489; Other ( Other Identifier: GENERATION HD2 )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
• Supporting Materials: Study Protocol

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Hoffmann-La Roche
• Verification Date: April 2024